Israeli scientists report (Thursday 15 September) in Human Reproduction that they have successfully transplanted whole frozen and thawed ovaries in sheep, retrieved oocytes from these ovaries and triggered them in the laboratory into early embryonic development. This could one day become a feasible treatment for women who have lost their fertility and may also have potential applications for other human organ transplants.

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Israeli scientists report (Thursday 15 September) in HumanReproduction[1] that they have successfully transplanted whole frozenand thawed ovaries in sheep, retrieved oocytes from these ovaries andtriggered them in the laboratory into early embryonic development.

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Follow-up tests showed that the ovaries in the two sheep from whichoocytes were recovered were still functioning normally three yearslater.

Lead author Dr Amir Arav, senior scientist at the Institute of AnimalScience, Agriculture Research Organisation, Bet Dagan, said that theseresults demonstrate for the first time that it is possible in a largeanimal species, to remove, freeze, thaw and replace ovaries, obtainoocytes and maintain normal ovarian long-term function. This holds outhope that this approach could become a feasible treatment for womenfacing premature ovarian failure, and furthermore, that the advancesthey have demonstrated from new freezing techniques may have potentialfor other human organ transplants, which are currently done using onlyfresh grafts.

Co-author Yehudit Nathan, program manager at Core Dynamics, the biotechcompany that funded and provided the scientific and technologicalexpertise for the project, said the next goal was to attempt totransplant ovaries in women at risk of losing their fertility.

"There is a lot of research still to be done, but we hope that it willnot take more than a few years for this to become a practicable optionfor women, such as young cancer patients, who would otherwise be leftinfertile after their treatment," she said.

Whole ovary autologous transplants have already been attempted twice inwomen -- in 1987 and 2004 -- in both cases into the upper arm, but inneither case was the ovary frozen and thawed first[2].

Another much-researched option is freezing and transplanting thawedovarian tissue. Two babies have been born using this technique[3].However, adhesions and the loss of blood to the ovarian follicles thatoccurs during the interval before new blood vessels are being formed,remain major obstacles.

The first aim of the Israeli team was to test in vitro whetherwhole ovaries from sheep, together with the blood vessels, couldsurvive the freeze-thaw process using a technique they have developedthat allows precise control over the propagation of ice crystals duringthe freezing process, thus reducing the damage caused to cells byconventional methods[4]. Sheep were chosen because their ovaries aresimilar to those of humans. The technique worked -- the frozen-thawedovaries produced comparable numbers of follicles as the fresh controlovaries.

The next objective was to see if they could remove, freeze and thaw theright ovary from eight sheep, including the vascular pedicles (theattachment that contains the main blood vessels), and replace the ovaryup to a fortnight later, either at the original site or by grafting iton to the pedicle of the (removed) left ovary. Of the five sheep wherenormal blood flow resumed immediately, indicating that the transplanthad succeeded, one had severe adhesions and it was not possible toattempt oocyte collection, but two yielded one oocyte each and repeataspiration four months later produced four more oocytes from one ofthese sheep.

All six ooctyes were activated parthenogenically using chemicals thatmimic the normal fertilisation process, and developed into 8-cellembryos.

"We used parthenogenic activation as we had only a low number ofoocytes and because IVF success in sheep depends on the quality of theram's sperm. This way, we knew that the development of the embryodepended solely on the quality of the ooctye," said Dr Arav.

Two years after transplantation the researchers carried outmagnetic resonance imaging (MRI) on one sheep with a transplanted ovaryand one untreated control sheep. It showed that the transplanted ovarycontained small oocyte follicles, and although a little smaller thanthe ovary in the control sheep it was within the normal range. Theblood vessels were also intact.

"Adhesions on the transplant might interfere with natural conception sopregnancy may require IVF techniques, but we have been able todemonstrate long-term intact organ cryopreservation with restoredfunction following thawing and transplantation, in a large animal foraround 36 months post-transplantation," said Dr Arav. "This approachcould revolutionise the field of cryopreservation for diverse humanapplications, such as organ transplants, as well as helping women whoface the loss of their fertility."

The research may also have far-reaching applications for animals. Theteam recently froze the ovary of the Gazelle gazelle acaiae, anendangered sub-specie of the Gazelle gazelle, so that it can betransplanted in the future into an immune-suppressed surrogate.

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[1] Oocyte recovery, embryo development and ovarian function aftercryopreservation and transplantation of whole sheep ovary. HumanReproduction. doi:10.1093/humrep/dei278.[2] Whole ovary transplants: First done in 1987 on an 18-year-oldcancer patient, but there was a 3 month delay in performing theoperation while a prosthesis could create a space for the ovary in thearm. The second, Hilders et al, Cancer Vol 101 Issue 12 pp2771-2778 15December 2004.[3] The first baby born from frozen ovarian cortex and transplantationwas reported by Donnez et al, The Lancet. Vol. 364, Issue 9451, 11December 2004, pp 2091-2092. The second was reported by Meirow et al,New England Journal of Medicine, 2005 252: 318-321, July 21 2005.[4] The cryopreservation method involved was directional freezing,using Core Dynamics' new multi-thermal gradient (MGT) technology.

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